Neuroinflammation is emerging as a central pathophysiological mediator in the neurodegenerative processes of many chronic neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis, and Parkinson's disease. In particular, neuroinflammatory mechanisms pertaining to the progression of Parkinson's disease are current focal points of investigation since mitochondrial dysfunction and oxidative stress can not completely explain the chronic degenerative progression in the nigrostriatal dopaminergic system that ultimately results in irreversible debilitating motor deficits. Interestingly, postmortem analysis of the Parkinson's disease brain reveals signs of inflammatory processes including microglial activation and induction of proinflammatory factors such as TNFa and NF-kB along with loss of dopaminergic neurons in the nigra. Similarly, recent evidence from experimental models of Parkinson's disease clearly demonstrates microglial activation and cytokine release in the nigrostriatal region during exposure to neurotoxic insults. However, the cellular events which regulate the neuroinflammatory cascade in microglia during neurotoxic insults and the role of microglia mediated inflammation in the progression of nigral degenerative processes are not completely understood. As depicted in the preliminary data, we have identified a member of the novel PKC isoform family, protein kinase C-delta (PKCd), as a critical regulator of release of a key proinflammatory cytokine TNFa from microglial cells. We also demonstrated that the kinase also serves as a proapoptotic kinase in dopaminergic neurons during inflammatory insults. In this proposal, we will extend our preliminary findings by pursuing the following specific aims: (i) To determine the differential mode of activation of PKCd in neuronal and microglial cells using cell culture models of Parkinson's disease and to examine the role of PKCd in regulating the production of proinflammatory cytokines (e.g., TNFa) in microglial cells;ii) To examine the role of PKCd in cytokine production and microglial activation in the nigrostriatal dopaminergic system using animal models of Parkinson's disease;iii) To determine whether neuroinflammatory cytokines upregulate the expression of PKCd in microglia to sustain and amplify the inflammatory cascade in a NF-kB dependent manner;and iv) To determine whether neuroinflammatory response from microglia can induce degeneration of nigral dopaminergic neurons through proteolytic activation of PKCd in animal models of Parkinson's disease. These specific objectives will be explored using various cellular and molecular biological approaches in neuroinflammatory models of Parkinson's disease. This systematic approach will help to unravel the key molecular mechanisms that regulate the neuroinflammatory cascade in microglia during the progressive degeneration of nigral dopaminergic neurons in Parkinson's disease. Ultimately, these mechanistic studies will translate into innovative therapeutic interventions for this progressively debilitating neurodegenerative disorder. PUBLIC HEALTH RELEVANCE: Parkinson's disease is a chronic and progressive neurodegenerative disorder affecting millions worldwide. The cellular mechanisms underlying the course of progression of nigral dopaminergic neurons is not yet understood. This proposal focuses on a protein kinase isoform specific cell signaling pathway that might play a role in amplification of the neuroinflammatory cascade in microglial cells in the nigrostriatal system. Understanding the cellular mechanisms of proinflammatory events responsible for progression of nigral degeneration will ultimately result in development of therapeutic strategies that will delay or halt the course of Parkinson's disease.